The candidate's long-term career goal is to combine his clinical interests in retinal diseases with his research interests in molecular biology. Washington University in general, and the sponsor's laboratory in particular, provides an exceptional setting for the candidate to pursue this goal. The sponsor's laboratory is a vigorous intellectual environment where many important contributions have been made in understanding the structure and function of the retinoblastoma protein (Rb) in health and disease. Further, the sponsor has an outstanding record of training successful clinician-scientists. The candidate's research will focus on the normal structure and function of Rb. While Rb was initially discovered through its role in the development of retinal tumors, it is now clear that Rb plays an important role in normal growth and differentiation of the retina. Understanding the normal function of Rb is likely to have significant implications not only for retinoblastoma, but also for macular and retinal degenerations, photoreceptor regeneration, and retinal transplantation. The candidate proposes a series of experiments to further elucidate the interaction between Rb and the E2F family of transcription factors. This interaction appears to be critical for cell cycle regulation and cellular differentiation. When Rb binds E2Fs, it blocks transcription from cell cycle genes that have E2F sites. In this proposal, the candidate will use a wide range of techniques, including transfection assays, and in vitro and in vivo binding studies to address the following specific aims: (1) determine regions in domains A and B of Rb that are responsible for transcriptional repression, (2) determine regions in domains A and B that mediate interdomain binding to form the active repressor motif, and (3) identify retina-specific transcription factors that are inhibited by Rb.